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Ann Thorac Surg 2003;75:465-466
© 2003 The Society of Thoracic Surgeons
Division of Cardiothoracic Surgery, University of California, San Diego, 200 West Arbor Dr, MC Suite 8892, San Diego, CA 92103-8892, USA
e-mail: pthistlethwaite{at}ucsd.edu
Although cardiac surgeons encounter calcific degenerative aortic valve disease on a frequent basis, little is known about the molecular causes of this disease. The study by Dr Jian and colleagues presents convincing evidence that transforming growth factor-ß1 (TGF-ß1) may be an important piece in the puzzle of the etiology of this disease.
Clues as to the causes of calcific aortic valve degeneration are revealed by pathologic analysis of diseased cusps removed at the time of valve replacement. In normal circumstances, aortic valve leaflets are composed of three principal layers: the ventricularis at the inflow surface, the spongiosa in the center, and the fibrosa at the outflow surface. The extracellular matrix components of these layers have been well characterized: the ventricularis contains radially aligned collagen and is rich in elastin; the spongiosa is primarily composed of glycosaminoglycans with some collagen; and the fibrosa contains densely packed collagen fibers aligned in parallel with the free edge of the valve cusp [1]. In calcific degeneration, five basic processes are observed: (1) focal endothelial damage of the fibrosa or outflow tract side; (2) inflammatory cellular infiltration of damaged sites with macrophages; (3) vascular smooth muscle transformation into an osteogenic phenotype making these cells capable of initiating mineralization; (4) vascular smooth muscle cell apoptosis with vesicle formation; (5) apatite nucleation of these sites with calcification of devitalized cells [2]. Thus the calcified valve nodules we encounter as surgeons represent focal areas of cell death, petrification of cellular degradation products with calcium, and deposition of extracellular matrix proteins commonly associated with bone.
Why do apoptotic cells and cellular debris become calcified instead of resorbed? The conversion of vascular smooth muscle cells into an osteoblastic phenotype appears central to this process. Extracellular proteins common to bone have been isolated from degenerating aortic valves including, osteocalcin, osteopontin, bone morphogenetic proteins, matrix metalloproteinases 2 and 9, tenascin-C, and matrix Gla protein [3–5]. It is speculated that the normal "checks and balances" between these positive and negative regulators of bone formation stimulates the calcification process. A careful assessment of both transgenic and knockout mice that either overexpress or lack the ability to produce these factors will shed light on which of these are truly causal of the mineralization process.
Dr Jian and colleagues have identified high levels of TGF-ß1 in calcified valve nodules and demonstrate the TGF-ß1 stimulates aortic valve interstitial cell in culture to aggregate, induce cellular apoptosis, and calcify. These experiments suggest that this bone/smooth muscle cell factor may play a role in the cascade of cellular death and transformation. It opens the doors to testing agents which block TGF-ß production, release, and function for ability to prevent valve calcification. The molecular dissection of this surgical disease has begun.
References
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  C. Y. Y. Yip, J.-H. Chen, R. Zhao, and C. A. Simmons Calcification by Valve Interstitial Cells Is Regulated by the Stiffness of the Extracellular Matrix Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 936 - 942. [Abstract] [Full Text] [PDF]
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N. M. Rajamannan Calcific Aortic Stenosis: Lessons Learned From Experimental and Clinical Studies Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 162 - 168. [Abstract] [Full Text] [PDF]
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P. Sucosky, K. Balachandran, A. Elhammali, H. Jo, and A. P. Yoganathan Altered Shear Stress Stimulates Upregulation of Endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-{beta}1-Dependent Pathway Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 254 - 260. [Abstract] [Full Text] [PDF]
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 R. J. Levy Serotonin Transporter Mechanisms and Cardiac Disease Circulation, January 3, 2006; 113(1): 2 - 4. [Full Text] [PDF]
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